Design, Synthesis, and Biological Evaluation of Indoline and Indole Derivatives as Potent and Selective α1A-Adrenoceptor Antagonists
文摘
A series of indoline and indole derivatives were designed, synthesized, and evaluated as selective α<sub>1Asub>-adrenergic receptor (α<sub>1Asub>-AR) antagonists for the treatment of benign prostatic hyperplasia (BPH). In this study, two highly selective and potent α<sub>1Asub>-AR antagonists, compounds (R)-14r (IC<sub>50sub> = 2.7 nM, α<sub>1Bsub>/α<sub>1Asub> = 640.1, α<sub>1Dsub>/α<sub>1Asub> = 408.2) and (R)-23l (IC<sub>50sub> = 1.9 nM, α<sub>1Bsub>/α<sub>1Asub> = 1506, α<sub>1Dsub>/α<sub>1Asub> = 249.6), which exhibited similar activities and better selectivities in cell-based calcium assays as compared with the marketed drug silodosin (IC<sub>50sub> = 1.9 nM, α<sub>1Bsub>/α<sub>1Asub> = 285.9, α<sub>1Dsub>/α<sub>1Asub> = 14.4), were identified. In the functional assays with isolated rat tissues, compounds (R)-14r and (R)-23l also showed high potency and uroselectivity. Most importantly, (R)-14r and (R)-23l can significantly decrease the micturition frequency and increase the mean voided volume of the BPH rats in a dose-dependent manner, making them worthy of further investigation for the development of anti-BPH agents.